ESC Heart Failure - 2022 - Montero - Time Course Factors Related To and Prognostic Impact of Venoarterial Extracorporeal

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ESC HEART FAILURE ORIGINAL ARTICLE
ESC Heart Failure (2022)
Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/ehf2.14132
Time course, factors related to, and prognostic impact

of venoarterial extracorporeal membrane flow in
cardiogenic shock
Santiago Montero1,2 , Mercedes Rivas-Lasarte3, Florent Huang2, Juliette Chommeloux2,
Pierre Demondion4,5, Nicolas Bréchot2,5, Guillaume Hékimian2,5, Guillaume Franchineau2,5,
Romain Persichini6, Charles-Édouard Luyt2,5, Cosme Garcia-Garcia1, Antoni Bayes-Genis1,
Guillaume Lebreton4,5, Juan Cinca7, Pascal Leprince4,5, Alain Combes2,5, Jesus Alvarez-Garcia8 and
Matthieu Schmidt2,5*
1
Acute Cardiovascular Care Unit, Cardiology, Hospital Germans Trias i Pujol, Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain; 2Medical
Intensive Care Unit, Assistance Publique–Hôpitaux de Paris, Pitié–Salpêtrière Hospital, Paris Cedex 13, France; 3Advanced Heart Failure and Heart Transplant Unit,
Cardiology Department, Hospital Universitario Puerta de Hierro Majadahonda, CIBERCV, Madrid, Spain; 4Thoracic and Cardiovascular Department, Assistance Publique–
Hôpitaux de Paris, Pitié–Salpêtrière Hospital, Paris Cedex 13, France; 5Institute of Cardiometabolism and Nutrition, Sorbonne Université, INSERM UMRS_1166-iCAN, 75651,
Paris Cedex 13, France; 6Medical–Surgical Intensive Care Unit, CHU de La Réunion, Felix-Guyon Hospital, Saint Denis, La Réunion, France; 7Cardiology Department, Hospital
de la Santa Creu i Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain; and 8Cardiology Department, Hospital Ramón y Cajal, Centro de Investigación en Red en
Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
Abstract
Aims Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is currently one of the most used devices in refractory
cardiogenic shock. However, there is a lack of evidence on how to set the ‘optimal’ flow. We aimed to describe the evolution of
VA-ECMO flows in a cardiogenic shock population and determine the risk factors of ‘high-ECMO flow’.
Methods and results A 7 year database of patients supported with VA-ECMO was used. Based on the median flow during
the first 48 h of the VA-ECMO run, patients were classified as ‘high-flow’ or ‘low-flow’, respectively, when median ECMO flow
was ≥3.6 or <3.6 L/min. Outcomes included rates of ventilator-associated pneumonia, ECMO-related complications, days on
ECMO, days on mechanical ventilation, intensive care unit and hospitalization lengths of stay, and in-hospital and 60 day mor-
tality. Risk factors of high-ECMO flow were assessed using univariate and multivariate cox regression. The study population
included 209 patients on VA-ECMO, median age was 51 (40–59) years, and 78% were males. The most frequent aetiology lead-
ing to cardiogenic shock was end-stage dilated cardiomyopathy (57%), followed by acute myocardial infarction (23%) and
fulminant myocarditis (17%). Among the 209 patients, 105 (50%) were classified as ‘high-flow’. This group had a higher rate
of ischaemic aetiology (16% vs. 30%, P = 0.023) and was sicker at admission, in terms of worse Simplified Acute Physiology
Score II score [40 (26–58) vs. 56 (42–74), P < 0.001], higher lactate [3.6 (2.2–5.8) mmol/L vs. 5.2 (3–9.7) mmol/L,
P < 0.001], and higher aspartate aminotransferase [97 (41–375) U/L vs. 309 (85–939) U/L, P < 0.001], among others. The
‘low-flow’ group had less ventilator-associated pneumonia (40% vs. 59%, P = 0.007) and less days on mechanical ventilation
[4 (1.5–7.5) vs. 6 (3–12) days, P = 0.009]. No differences were found in lengths of stay or survival according to the ECMO
flow. The multivariate analysis showed that risk factors independently associated with ‘high-flow’ were mechanical ventilation
at cannulation [odds ratio (OR) 3.9, 95% confidence interval (CI) 2.1–7.1] and pre-ECMO lactate (OR 1.1, 95% CI 1.0–1.2).
Conclusions In patients with refractory cardiogenic shock supported with VA-ECMO, sicker patients had higher support since
early phases, presenting thereafter higher rates of ventilator-associated pneumonia but similar survival compared with
patients with lower flows.
Keywords Cardiogenic shock; Extracorporeal membrane oxygenation; ECMO flow; Mechanical ventilation; Outcome
Received: 31 March 2022; Revised: 6 August 2022; Accepted: 18 August 2022
*Correspondence to: Matthieu Schmidt, MD, PhD, Médecine Intensive Réanimation, iCAN, Institute of Cardiometabolism and Nutrition, Hôpital de la Pitié–Salpêtrière, 47, bd
de l’Hôpital, 75651 Paris Cedex 13, France. Tel: +33 (0)142162937; Fax: +33 (0)1 42163817. Email: [email protected]
Dr Jesus Alvarez-Garcia and Dr Matthieu Schmidt contributed equally to this study.
© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,
provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
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2 S. Montero et al.
Introduction CS was defined as sustained systolic blood

pressure < 90 mmHg or requiring vasoactive drugs to main-
Refractory cardiogenic shock (CS) represents the worst clini- tain it ≥90 mmHg, with concomitant evidence of tissue
cal scenario of acute heart failure, consisting of profound sys- hypoperfusion.12,13 CS was considered refractory when
temic hypoperfusion due to a primary cardiac dysfunction.1,2 acute cardiovascular failure developed despite high-dose
In such cases, venoarterial extracorporeal membrane oxygen- catecholamine infusion (epinephrine ≥ 1 μg/kg/min or
ation (VA-ECMO) has arisen as one of the most used devices dobutamine ≥ 15 μg/kg/min or norepinephrine ≥ 1 μg/kg/
for mechanical circulatory support (MCS), given its ease of min). Exclusion criteria were patients aged <18 or
deployment and widespread availability.3,4 >75 years old, cannulated during cardiopulmonary resuscita-
Management of VA-ECMO requires a high level of exper- tion, post-cardiotomy, or patients with atypical CS aetiol-
tise and appropriate assessment of multiple elements, ogies. In addition, we excluded patients in cardiac arrest that
including ventilator parameters, sedation, anticoagulation, required intubation before starting ECMO, those with ECMO
pharmacokinetics, and optimal VA-ECMO performance to for ≤24 h, and patients who were transferred late to our cen-
avoid complications. In VA-ECMO-supported patients, the tre without information about mechanical ventilation (MV)
blood flow goes in a non-physiological, retrograde direction details of the early part of the ECMO run. Moreover, patients
that increases left ventricular (LV) afterload and LV with no data regarding ECMO flow on Days 1 (D1) and 2 (D2)
end-diastolic pressure, thus favouring the development of were also excluded (see Supporting Information, Table S1 for
pulmonary oedema. The drawbacks of this ‘reverse’ flow additional information regarding basal characteristics of the
have been consistently reported,5,6 and several strategies to latter).
‘unload’ the left ventricle have been proposed.7,8 Pharmaco- The study complies with the Declaration of Helsinki and is
logical unloading with inotropic drugs and reduction of the in accordance with the ethical standards of our hospital’s in-
VA-ECMO flow are commonly the first steps.9 Nevertheless, stitutional review board and French law. Informed consent
these measures are often insufficient, and additional was not necessary due to the retrospective and observational
unloading with devices such as intra-aortic balloon pump design of this study. The National Commission for Informatics
(IABP) or Impella is frequently needed. The choice of the and Liberties approved this study (No. 1950673).
unloading strategy usually depends on the clinician’s experi-
ence, centre availability, and CS aetiology. Moreover,
refractory CS is a dynamic clinical condition that demands Extracorporeal membrane oxygenation
continuous assessment of the VA-ECMO performance. management
However, there is a lack of evidence on what the ‘optimal’
ECMO flow is, and how it can be assessed. Because a reason- VA-ECMO cannulas were inserted by trained cardiovascular
able strategy would consist of assuring ‘the minimum flow to surgeons with femoral–femoral 23F to 29F–15F to 18F cannu-
maintain organ perfusion’,10 a sustained high flow beyond las as previously described.14 An additional 7F catheter was
the early phases of CS could turn out to be deleterious. systematically inserted into the femoral artery to prevent
In the present work, we sought to describe the evolution leg ischaemia. For highly unstable patients, our mobile ECMO
of VA-ECMO flow in a CS population according to the degree team travelled to primary-care hospitals to implant the de-
of support (‘low-flow’ vs. ‘high-flow’) during the first 48 h. vice at the bedside and to transport the patient to our centre.
Secondly, we analysed the unloading strategy, the factors as- The management of VA-ECMO, including ECMO flow,
sociated with ‘high-flow’, and the impact on short-term depended on the physician in charge. As is usual practice in
outcomes. our centre, most patients were initially managed with an
unloading strategy that usually began with implantation of
an IABP combined with ECMO in the contralateral femoral
access, at the same time as VA-ECMO implantation. If despite
routine unloading measures, the patient develops progres-
Methods sive pulmonary oedema or the aortic valve opens only
sporadically, we would consider upgrading to Impella.
Study population and design
This is a retrospective, single-centre study including patients Data collection

in refractory CS supported with peripheral VA-ECMO admitted
at La Pitié-Salpêtrière University Hospital in Paris between 1 At intensive care unit (ICU) admission, we collected demo-
January 2010 and 31 December 2016. The database for this graphic information, cardiovascular risk factors, main comor-
study has previously been used to analyse the impact of an bidities, and Simplified Acute Physiology Score (SAPS) II.
awake VA-ECMO strategy published elsewhere.11 During the pre-ECMO period, the Sequential Organ Failure

DOI: 10.1002/ehf2.14132
Time course of ECMO flow in cardiogenic shock 3
Assessment (SOFA) score, the Survival after Veno-Arterial Results

ECMO (SAVE) score,15 the inotrope score, the Interagency
Registry for Mechanically Assisted Circulatory Support Clinical characteristics and time course of
(INTERMACS) classification, the Society for Cardiovascular
extracorporeal membrane oxygenation flow in
Angiography and Interventions (SCAI) classification of CS,16
the study population
cannulation by the mobile ECMO team, haemodynamic pa-
rameters, blood–gas analysis, renal and liver functions, left
Two hundred and nine patients were included in the analysis
ventricular ejection fraction (LVEF), and intubation status
(Figure 1). Overall, the median age was 51 (40–59), where
were noted. Because all patients had digitized medical charts,
78% were males, and the median SAPS II was 51 (32–66) (Ta-
ECMO flow, intubation and MV status, and need of renal re-
ble 1). The most frequent aetiology leading to CS was
placement therapy (RRT) were recorded daily for a maximum
end-stage dilated cardiomyopathy (DCM) (57%), followed by
of 14 days on ECMO. According to the time on MV during the
acute myocardial infarction (AMI) (23%) and fulminant myo-
ECMO run, patients were categorized as ‘awake’ or ‘non-
carditis (17%).
awake’ ECMO when time on invasive MV was ≤50% or
One hundred and four (50%) patients were classified as
>50% of the total time on VA-ECMO run, respectively, as de-
‘low-flow’ and 105 (50%) as ‘high-flow’. In general, the me-
scribed previously.11
dian ECMO flow showed a tendency to decrease, from the
Based on the median flow through the first 48 h of
initial 3.7 (3.0–4.2) L/min on Day 1 to 3.2 (2.7–3.8) L/min
VA-ECMO run of the whole cohort, patients were classified
on Day 6. Median flows between both groups were
as ‘high-flow’ or ‘low-flow’ if ECMO flow was ≥3.6 or
continuously lower in ‘low-flow’ patients at any time point,
<3.6 L/min, respectively.
with the ‘low-flow’ group maintaining VA-ECMO flows around
3.0–3.1 L/min. Figure 2A shows the evolution of the
VA-ECMO support during the first 14 days for these groups.
Compared with the ‘low-flow’ patients, those with ‘high-flow’
Outcomes
had similar demographic and cardiovascular risk profiles, but
ischaemic aetiology was more frequent. Moreover, they had
Complications during ECMO support included rates of
greater ICU severity scores and a lower SAVE score. In
ventilator-associated pneumonia (VAP), stroke, leg ischaemia,
addition, MV at cannulation and cannulation by the mobile
bacteraemia, cannula site infection, vena cava thrombosis,
ECMO unit was more frequent in the ‘high-flow’ group
and conversion to central ECMO. We also reported days on
(Table 1).
ECMO, days on MV, and ICU and hospitalization length of
stay. Lastly, bridge to heart transplant (HTx), time from ECMO
to HTx, and in-hospital and 60 day mortality were noted. Factors related to high extracorporeal membrane
Details about ECMO-related complications are reported in oxygenation flows
the supporting information.
In the multivariate analysis, MV at implantation and
pre-ECMO lactate were independently associated with high
ECMO-flows {with respective odds ratio [OR] 3.9 [95% confi-
Statistical analysis dence interval (CI) 2.1–7.1], P < 0.001 and 1.1 [95% CI 1.0–
1.2], P < 0.001}.
Continuous variables were expressed as median [interquartile
range (IQR)] and compared with Wilcoxon rank-sum tests.
Categorical variables were expressed as numbers (percent- Extracorporeal membrane oxygenation
age) and compared with χ 2 tests. management
To identify the factors related to ‘high-flow’ support, a
multivariate stepwise logistic regression model was con- More than 40% of all patients were managed with an
structed including the baseline variables found to be associ- awake strategy, with a higher rate in the ‘low-flow’ group
ated in the univariate analysis with a P value < 0.10. (52% vs. 30%, P < 0.001). Additionally, 54% required RRT,
Kaplan–Meier curves were used to evaluate the associa- with higher needs in the ‘high-flow’ group (41% vs. 66%,
tion between the VA-ECMO flow classification with 60 day P < 0.001).
mortality. Almost 70% of the study population was managed with
All statistical tests were two-sided, with a P value ≤ 0.05 LV unloading with no differences between the two groups
considered significant. Statistical analysis was computed with (Table 1). Regarding the type of LV unloading, IABP was the
STATA software, Version 13.1 (Stata Corp, College Station, most employed device (94%). Baseline characteristics were
Texas). similar among the non-unloaded and unloaded subgroups,

DOI: 10.1002/ehf2.14132
4 S. Montero et al.
Figure 1 Flow chart of the study population. CS, cardiogenic shock; D1, Day 1; D2, Day 2; eCPR, ECMO-rescued cardiopulmonary resuscitation; MV,
mechanical ventilation; VA-ECMO, venoarterial extracorporeal membrane oxygenation.
except for the predominance of males (83% vs. 67%, found in the ICU length of stay or the days of hospitaliza-
P = 0.011) and non-myocarditis aetiology in the unloaded tion. The ‘low-flow’ group was more frequently bridged to
subgroup (Supporting Information, Table S2). Unloaded transplant during the index admission (33% vs. 18%,
patients were managed with higher flows (Figure 2B) and P = 0.015), with no differences in rates of bridging to left
higher doses of inotropic drugs from Day 3 to Day 5, and they ventricular assist device (LVAD) (24% vs. 20%, P = 0.481)
were also more frequently managed with an awake ECMO (Table 2).
strategy (47% vs. 29%, P = 0.012) (Supporting Information, On the other hand, non-unloaded patients were less fre-
Table S3). quently bridged to HTx (21% vs. 41%), and the waiting time
from ECMO implantation to HTx was significantly shorter [5
(1–15) days vs. 13 (5–165) days, P = 0.031]. Outcomes accord-
Outcomes ing to mechanical LV unloading are reported in Supporting In-
formation, Table S3.
Half of the study population presented with at least one VAP Comparison among in-hospital survivors did not show sig-
during admission, followed by cannula site infection (42%) nificant differences in either MV or VA-ECMO duration nor
and bacteraemia (30%). Patients with ‘high-flow’ had more in ICU or hospitalization length of stay. In-hospital survivors
VAP and leg ischaemia episodes than ‘low-flow’ patients, did not present significant differences in rates of transplant
but fewer bacteraemia and cannula site infections. or LVAD (Supporting Information, Table S4).
The median length of VA-ECMO support was 9 (5–15) Finally, in-hospital mortality of the study population was
days, with no differences between groups. The median 46%, with a non-significant lower mortality rate in the ‘low-
length of time on MV was 4 (2–10) days, with a signifi- flow’ group (41% vs. 51%, respectively, P = 0.144). Mortality
cantly shorter time in the ‘low-flow’ group [4 (1.5–7.5) vs. at 60 days was comparable in the two groups (log-rank
6 (3–12) days, P = 0.009, respectively]. No differences were P = 0.222) (Figure 3).

DOI: 10.1002/ehf2.14132
Table 1 Baseline characteristics and outcomes of the study population according to the median VA-ECMO flow in the first 48 h
Variable Study population (n = 209) Low-flow (n = 104; 50%) High-flow (n = 105; 50%) P value
Age, years 51 (40–59) 51 (37–58) 52 (42–61) 0.194
Male sex 162 (78) 80 (77) 82 (78) 0.839
Body mass index 25.2 (23.1–27.8) 25.2 (22.2–27.6) 25.3 (23.4 29.4) 0.216
Diabetes mellitus 48 (23) 24 (23) 24 (23) 0.970
Dyslipidaemia 38 (18) 15 (14) 23 (22) 0.161
Pre-ECMO data
Aetiology 0.023
Dilated cardiomyopathy 119 (57) 69 (66) 50 (48)
Acute myocardial infarction 48 (23) 17 (16) 31 (30)
Fulminant myocarditis 36 (17) 14 (13) 22 (21)
Other 6 (3) 4 (4) 2 (2)
SAPS II 51 (32–66) 40 (26–58) 56 (42–74) <0.001
APACHE II 23 (12–32) 15 (9–28) 29 (17–35) <0.001
SOFA pre-implantation 10 (6–13) 8 (5–12) 12 (8–14) <0.001
SAVE score 3 ( 8 to 1) 1 ( 5 to 1) 6 ( 10 to 0) <0.001
INTERMACS category 0.047
I 115 (55) 49 (48) 66 (63)
II 79 (38) 44 (43) 35 (33)
SCAI classification <0.000
Stage D 59 (28) 44 (42) 15 (14)
Stage E 150 (72) 60 (58) 90 (86)
MV at implantation 114 (55) 38 (37) 76 (73) <0.001
Inotrope score, μg/kg/min 37 (11–102) 18 (11–72) 57 (15–128) 0.029
pH 7.41 (7.26–7.46) 7.43 (7.36–7.49) 7.35 (7.20–7.44) <0.001
Lactate pre-ECMO, mmol/L 4.5 (2.5–7) 3.6 (2.2–5.8) 5.2 (3–9.7) <0.001
LVEF, % 15 (10–20) 15 (10–15) 15 (10–20) 0.144
Creatinine, mmol/L 135 (100–185) 125 (98–175) 147 (105–196) 0.078
AST, U/L 158 (52–720) 97 (41–375) 309 (85–939) <0.001
Bilirubin, mmol/L 25 (14–39) 22 (13–36) 26 (15–41) 0.249
Mobile ECMO unit 62 (30) 22 (21) 40 (38) 0.007
Management
ECMO flow D3, L/min 3.5 (2.9–4.2) 3.1 (2.6–3.5) 4.2 (3.6–4.7) <0.001
ECMO flow D5, L/min 3.3 (2.8–4) 3.1 (2.6–3.4) 3.7 (3.2–4.3) <0.001
ECMO flow D7, L/min 3.3 (2.7–3.9) 3.1 (2.7–3.5) 3.7 (2.9–4.3) 0.001
ECMO flow D14, L/min 3.5 (2.8–4) 3.2 (2.7–3.8) 3.7 (2.9–4.2) 0.13
LV unloading 139 (67) 72 (69) 67 (64) 0.406
a
Awake status <0.001
Awake 85 (41) 54 (52) 31 (30)
Non-awake 124 (59) 50 (48) 74 (70)
RRT 112 (54) 43 (41) 69 (66) <0.001
Note: Values are expressed as median (interquartile range) or n (%). Abbreviations: APACHE II, Acute Physiology And Chronic Health Eval-
uation II; AST, aspartate aminotransferase; D1, Day 1; D2, Day 2; D3, Day 3; D4, Day 4; D5, Day 5; D6, Day 6; D7, Day 7; D14, Day 14;
ECMO, extracorporeal membrane oxygenation; INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support; LV, left
ventricular; LVEF, left ventricular ejection fraction; MV, mechanical ventilation; RRT, renal replacement therapy; SAPS II, Simplified Acute
Physiology Score II; SAVE, Survival after Veno-Arterial ECMO; SOFA, Sequential Organ Failure Assessment.
Definition: ≤50% of the time of ECMO support without MV or >50% of the time of ECMO support with MV.
a
Discussion the high-flow group. The independently associated factors

with higher ECMO support in the first 48 h were MV at im-
Main findings plantation and pre-ECMO lactate. Finally, the decision of
adding LV unloading was influenced by the aetiology of CS
To the best of our knowledge, this is the largest study to re- but did not affect survival in our cohort.
port the time course, factors related to, and prognostic im- Nowadays, there is a lack of solid recommendations re-
pact of ECMO flow on patients with VA-ECMO-supported regarding the proper VA-ECMO flow throughout the different
fractory CS. In our population, sicker patients at ECMO phases of CS. There is a variety of clinical practice recommen-
cannulation were managed with higher flows from early dations ranging from 60–80 mL/kg17 to 50–70 mL/kg,18 or
stages and the divergence of ECMO flows was kept from ini- even 5 L/min during the first 24 h.19 However, reported data
tial assessments during the first week of support. Whereas on VA-ECMO flows in MCS literature are scarce and
the so-called ‘high-flow’ group had higher rates of VAP, the heterogeneous.19–21 Theoretically, the amount of flow
‘low-flow’ had higher rates of ‘awake ECMO’ management needed may vary widely throughout VA-ECMO support de-
and fewer days of MV but eventually did not have signifi- pending on the CS phase and the clinical profile of patients.
cantly different short-term survival when compared with Thus, patients with a more profound CS at admission are sup-

DOI: 10.1002/ehf2.14132
6 S. Montero et al.
Figure 2 VA-ECMO support during the first 14 days showing the VA-ECMO flow in the ‘low flow’ vs. ‘high flow’ and unloaded vs. non-unloaded groups.
(Panel A) Differences in VA-ECMO flow are overt during the first 3 days, reaching differences of 1 L/min between groups. Thereafter, differences began
to shorten, mainly from D5. (Panel B) The VA-ECMO flows are not different in the early phases according to the unloading, but, thereafter, they tended
to be lower in the ‘non-unloaded’ group. The predominance of myocarditis, the lesser bridge to transplant in the index admission, and the lesser ino-
tropic support in early phases in the latter might suggest a perception of a lower severity by the treating physicians or a presumed prompt ECMO
explantation because of a nearly expected heart transplant or in self-limited aetiologies like myocarditis. ECMO, extracorporeal membrane
oxygenation.
posed to require a higher degree of VA-ECMO support, at the classical marker of tissular hypoperfusion. As such, the
least in the early phase. Similarly to our results, Truby et al. higher levels of lactate at cannulation in sicker patients may
reported a median flow of 3.61 ± 0.84 L/min in the first 2 h be logically associated with a higher degree of support in
in a study evaluating LV distension.21 the early phases. Patients mechanically ventilated at
Not surprisingly, the independent factors related to early VA-ECMO implantation are usually sicker, so again higher
‘high-flow’ were both related to clinical severity. Lactate is flows appear logical. Furthermore, MV at cannulation ap-

DOI: 10.1002/ehf2.14132
Table 2 Complications and outcomes of the study population most constant around 3.0–3.1 L/min in the ‘low-flow’ group.
according to the median VA-ECMO flow in the first 48 h
From D4 to D5, the differences began to decrease but re-
Study Low-flow High-flow mained constant until the end of the first week. Interestingly,
population (n = 104; (n = 105; P
despite having achieved practical normalization of levels of
(n = 209) 50%) 50%) value
lactate, the ‘high-flow’ group kept a higher degree of VA-
Complications
VAP 104 (50) 42 (40) 62 (59) 0.007
ECMO support after the acute phase was over, likely because
Stroke 35 (17) 18 (17) 17 (16) 0.829 of an increased perception of severity by the physicians in
Leg ischaemia 33 (16) 11 (11) 22 (21) 0.04 charge. Nevertheless, whether the worse prognosis was re-
Bacteraemia 63 (30) 39 (37) 24 (23) 0.021
Cannula site 87 (42) 52 (50) 35 (33) 0.015
lated to the initial greater severity or rather to the pulmonary
infection effects of higher afterload remains uncertain and warrants
Conversion to 17 (8) 7 (7) 10 (10) 0.460 future research.
central ECMO
Vena cava 32 (15) 15 (14) 17 (16) 0.723
In some circumstances, the severity of CS might drive to
thrombosis look for increasing VA-ECMO flows due to the refractoriness
Outcome measures of multiorgan failure. However, disproportionately high
Days on ECMO 9 (5–15) 9.5 (5.5–17) 9 (5–15) 0.747
Days on MV, total 4 (2–10) 4 (1.5–7.5) 6 (3–12) 0.009
VA-ECMO flows are not useful for improving microcirculation.
Days in ICU 22 (12–37) 22 (13–35) 21 (10–37) 0.515 This relates to the well-known lack of relationship between
Days of 37 (24–66) 41 (24–70) 36 (21–62) 0.302 macrocirculation and microcirculation22–24 and also corrobo-
hospitalization
Bridge to 53 (22) 34 (33) 19 (18) 0.015
rates the need of keeping VA-ECMO flow as low as possible
transplant on to maintain the aortic valve opened, the mean arterial
ECMO admission pressure > 65 mmHg, and normal lactate levels.
Bridge to LVAD 46 (22) 25 (24) 21 (20) 0.481
In-hospital 97 (46) 43 (41) 54 (51) 0.144
When comparing unloaded and non-unloaded patients,
mortality our findings showed a clear predominance of non-unloading
Dead 60-D 70 (34) 31 (30) 39 (38) 0.239 in myocarditis compared with AMI or DCM. Indeed, reduced
Note: Values are expressed as median (interquartile range) or n (%). VA-ECMO flow in non-unloaded patients from D2 to D7 is ac-
Abbreviations: 60-D, 60 days; ECMO, extracorporeal membrane
companied by less pharmacological unloading with dobuta-
oxygenation; ICU, intensive care unit; LVAD, left ventricular assist
device; MV, mechanical ventilation; VAP, ventilator-associated mine. Likely, that might be explained by a perception of a
pneumonia. lower severity by the treating physicians or a presumed
prompt ECMO weaning because of an expected HTx or
Figure 3 Kaplan–Meier survival curves at 60 days according to the
self-limited aetiologies like myocarditis.
VA-ECMO support in the first 48 h. Kaplan–Meier survival estimates for The increase in afterload of VA-ECMO has potentially harm-
patients with ‘low-flow’ (blue line) and ‘high-flow’ (red line) showed ful consequences at the pulmonary level. Alveolar oedema
lower mortality in the ‘low-flow’ group, although not reaching statistical produces local hypoxia, reduces the production of alveolar
significance. ECMO, extracorporeal membrane oxygenation. surfactant, produces local vasoconstriction, and, eventually,
induces self-perpetuation of the systemic inflammatory re-
sponse syndrome (SIRS).25–28 These pulmonary effects may
imply ventilator-induced lung injury and prolonged MV.21 In
our study, patients within the ‘low-flow’ group had a median
of two fewer days of MV than the ‘high-flow’ patients. Al-
though there may be clinical confounders, the previous path-
ophysiological effects could have contributed to prolonged
MV. We believe our study is hypothesis-generating and this
fact should be studied in specifically designed studies.
Clinical research on LV unloading has developed enor-
mously in recent years. However, data on VA-ECMO flow in
these studies are generally lacking and, in our opinion, are
critical to understand the best time for implantation and to
decide the best type of unloading device. In our experience,
IABP is generally enough in most patients to unload the LV,
especially if care is taken with disproportionate flows and
peared independently associated with reduced odds of LV distension.21 In our study, 94% of unloaded patients were
‘awake ECMO’ management,11 and that might also have unloaded with IABP, whereas only 12 patients (9%) needed
prognostic importance. Impella. The usefulness of the IABP in reducing afterload
Median VA-ECMO flows were more than 1 L higher in the and intraventricular pressures has been known for years, as
‘high-flow’ group during the first 72 h of support, keeping al- well as its effect in reducing pulmonary oedema or days of

DOI: 10.1002/ehf2.14132
8 S. Montero et al.
MV.29 However, there exists up to seven different methods of were not significantly different compared with patients with
unloading,6,8,30 from which the combination of VA-ECMO and lower flows. Independently related factors with a higher de-
Impella (i.e. ECMELLA/ECPELLA) has recently gained strong gree of VA-ECMO support were MV at cannulation and
attention.30–34 In most of these studies, the mortality risk pre-ECMO lactate. Future research is now warranted to ad-
was reduced when unloading was added, yet the high rates dress the specific and direct impact of higher flows in lung in-
of complications make its routine applicability dubious. At jury or length of MV, as well as the best timing and type of
present, there is still a lack of a randomized controlled trial unloading strategy for these patients.
(RCT) comparing these strategies to define the time of im-
plantation and the ideal clinical scenario.
In our study, the worse condition of the ‘high-flow’ group Acknowledgements
may have led to a greater number of complications. It is
known that the probability of infection while on ECMO in- We thank our medical colleagues from the referral centres in
creases with the severity of illness before initiation of the Ile-de-France region, French Caribbean, and Reunion
MCS,35,36 so higher rates of VAP might have been likely con- islands for reporting thorough and detailed information. We
ditioned by that. Yet, the potential impact of the pathophys- thank Theodore Chalkley for his grammatical revisions.
iological mechanisms explained above cannot be disregarded,
and therefore, our study aims to be suggestive rather than
conclusive in terms of respiratory outcomes. Specifically de-
signed RCTs evaluating different flow strategies in CS and mo-
Conflict of interest
dalities of LV unloading are now warranted to test if early
CEL reports personal fees from Carmat, Merck, Biomérieux,
high flows while on VA-ECMO do impact the length of MV,
Thermofischer Brahms, Bayer Healthcare, and Faron; AC re-
rates of VAP, or mortality.
ports personal fees from Getinge and Baxter; MS received
lecture fees from Getinge, Xenios, and Dräger. The other au-
Limitations thors declare that they have no competing interests.
First, the present study has the inherent limitations of a ret-

rospective design. However, we present the largest series of Funding
patients supported by VA-ECMO, reporting the VA-ECMO
flow data throughout the first 14 days of support. Secondly, S. Montero was funded by a 2016 Clinical Training Grant
unavoidable confounding factors prevent the conclusion of awarded by the European Society of Cardiology. The other
any definitive association between flows and outcomes. How- authors have no disclosures to declare.
ever, even though sicker patients are managed with higher
flows, it is plausible that an increased afterload may have
an impact on prolonged MV duration or rates of VAP because Supporting information
of greater lung injury. Thirdly, VA-ECMO flows are dependent
on preload, afterload, impeller revolutions, and static vari- Additional supporting information may be found online in the
ables like diameter and cannula length, and we lack this infor- Supporting Information section at the end of the article.
mation. Lastly, data on pulmonary congestion (x-ray, B-lines
on pulmonary echo, or pulmonary artery catheter Table S1. Baseline characteristics of the excluded population
information)37–39 would have enabled the comparison of flow compared to the study population.
impact and afterload on pulmonary pathophysiology but Table S2. Baseline characteristics according to the presence
were not available for this study. of mechanical left ventricular unloading during VA-ECMO
support.
Table S3. Management and outcomes according to the pres-
Conclusions ence of mechanical left ventricular unloading during
VA-ECMO support.
In patients with refractory CS supported with VA-ECMO, Table S4. Outcomes of the in-hospital survivors according to
sicker patients were managed with higher support from early the early ECMO flow.
phases. Patients with high flows had higher rates of VAP and Figure S1. Differences of VA-ECMO flow during the first
leg ischaemia, but their in-hospital and short-term survival 14 days according to in-hospital survival.

DOI: 10.1002/ehf2.14132
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DOI: 10.1002/ehf2.14132

ESC Heart Failure - 2022 - Montero - Time Course Factors Related To and Prognostic Impact of Venoarterial Extracorporeal

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20555822, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ehf2.14132 by Conricyt Fondo Institucional Del Conacyt, Wiley Online Library on [21/11/2022].

Time course, factors related to, and prognostic impact

Introduction CS was deﬁned as sustained systolic blood

This is a retrospective, single-centre study including patients Data collection

ESC Heart Failure (2022)

Assessment (SOFA) score, the Survival after Veno-Arterial Results

ESC Heart Failure (2022)

ESC Heart Failure (2022)

Discussion the high-ﬂow group. The independently associated factors

ESC Heart Failure (2022)

ESC Heart Failure (2022)

ESC Heart Failure (2022)

First, the present study has the inherent limitations of a ret-

ESC Heart Failure (2022)

ESC Heart Failure (2022)

ESC Heart Failure (2022)

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